Clinical and Experimental Data

A number of human and animal studies have been undertaken to determine which salt and water retaining hypothesis is most consistent with the observed facts. In 1968, Eisenberg measured the blood volume of nephrotic patients and

Q Renin/AII/Aldo^)

figure 2. The overflow hypothesis: renal salt and water retention in nephrotic syndrome. The pathology which produces increased glomerular permeability also produces intrarenal alterations which directly increase the reabsorption of salt and water by the kidney. Edema under these circumstances is associated with an expanded EABV and plasma volume.

Q Renin/AII/Aldo^)

figure 2. The overflow hypothesis: renal salt and water retention in nephrotic syndrome. The pathology which produces increased glomerular permeability also produces intrarenal alterations which directly increase the reabsorption of salt and water by the kidney. Edema under these circumstances is associated with an expanded EABV and plasma volume.

reported that it was usually normal or increased [5]. These findings were consistent with overflow physiology. However, the results of subsequent similar studies were equivocal; the blood volume of some nephrotic patients was reduced, in others it was normal, and in still others expanded [4]. Several factors may account for these conflicting results. First, as discussed, the hypovolemic underfill hypothesis is most likely to explain salt retention in patients with minimal change nephropathy. Many of the aforementioned studies included other forms of nephrotic syndrome. Intrinsic renal abnormalities which may cause renal salt retention are more likely when glomerulonephritis reduces renal perfusion and glomerular filtration. However, studies limited to patients with minimal change disease and normal glomerular filtration rates also often report normal or increased blood volumes. These results suggest that overflow pathophysiology may be operative in many nephrotic patients.

However, subsequent studies have raised a number of issues which confound and may invalidate blood volume measurements in patients with nephrotic syndrome. Total blood volume is usually determined by first measuring the plasma volume with a marker which is restricted to the vascular space, and then dividing this value by (1-Hct). Albumin, labeled with a radioactive molecule or a dye, is the most commonly utilized plasma volume marker. By definition, nephrotic patients have increased glomerular permeability to albumin.

Their systemic capillary beds may also develop increased albumin permeability. This greatly complicates the measurement of plasma volume. Furthermore, the blood volume calculation requires an accurate determination of the hematocrit. The hematocrit of normal individuals varies in different subcompartments of the circulatory system (i.e., the hematocrit in a peripheral vein is not the same as the hematocrit in renal venous blood or in the pulmonary artery). This normal hematocrit variation is greatly exaggerated in patients with nephrotic syndrome [4]. Also, orthostatic pooling of blood can reduce plasma volume when nephrotic patients stand [8]. All of these factors combine to confound blood volume measurements in nephrotic patients.

If all of the above issues could be resolved and the total blood volume of nephrotic patients accurately determined, it would still be difficult to use these results to prove or disprove one of the salt-retaining hypotheses. The underfill hypothesis requires a reduced EABV. It is possible for a low EABV to coexist with a normal or expanded total blood volume. Normally, EABV and total blood volume expand and contract symmetrically, but some pathologic disorders can dissociate changes in the size of these two volumes. For example, although EABV is usually reduced in patients with CHF or hepatic cirrhosis, their total blood volume is generally expanded. This could also be true in some patients with the nephrotic syndrome.

EABV cannot be measured directly, but several indirect markers of the relative size of this "space" do exist. The renin, angiotensin, and aldosterone levels generally reflect the EABV status. The plasma levels of these hormones decrease when the EABV expands and their concentrations increase when the EABV contracts. (The serum potassium concentration can also affect the renin and aldosterone levels.) Another indirect indicator of changes in the size of the EABV is the glomerular filtration fraction which changes in an inverse direction. EABV contraction increases the FF and EABV expansion reduces the FF.

If the underfill theory is operative in a patient with the nephrotic syndrome, then renin, aldosterone, and the FF should all increase. Although high renin and aldosterone levels and an elevated FF do exist in some nephrotic patients, these markers are normal or reduced in many others [16, 23]. Therefore, although the data in some patients is consistent with underfill physiology, in many others they suggest that overflow physiology exists.

Finally, several studies have evaluated changes in salt-retaining hormone levels produced by acute blood volume expansion. If renal salt and water retention is due to an underfilled circulation, then expansion of blood volume (and it is hoped the EABV) should reduce levels of salt retaining hormones and produce a diuresis. Intravenous infusions of colloid containing solutions and head out water immersion (which compresses venous capacitance vessels and expands central blood volume) have been utilized in efforts to expand the EABV

of nephrotic patients. However, the results are again inconclusive. Such volume expanding maneuvers do reduce renin and aldosterone levels and produce a diuresis in some nephrotic patients but in many others salt-retaining hormone levels remain high and antidiuresis persists [9,10,15].

In summary, evidence consistent with classic underfill pathophysiology exists in some patients with nephrotic syndrome, but the data is more compatible with the overflow hypothesis in many others. Underfilling may be somewhat more common in patients with minimal change disease. However, even in this most "ideal" subgroup many patients probably have overflow physiology. Consequently, many nephrotic patients may have intrinsic intrarenal alterations which stimulate salt and water retention. It must also be emphasized that the nephrotic syndrome is not a static condition and the salt retaining forces may change over time.

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